Many studies have shown that brain stem regions such as the nucleus raphe magnus and periaqueductal gray can control the inflow of sensory information to the spinal cord. It has recently been found that selective analgesia may result from stimulating these brain centers and that morphine analgesia may be mediated by the same mechanisms. Pathways implicated in this "descending control" extend from enkephalin-containing neurons in the mesencephalic central gray which project to serotonergic neurons in the nucleus raphe magnus, which in turn project to the spinal cord marginal zone (MZ) (lamina I), substantia gelatinosa (SG) (lamina II), and nucleus proprius (lamina V). However, many questions still remail unanswered, including 1) the types of neurotransmitters involved at the central nervous system (CNS) level; 2) the morphological and physiological substrates by which these descending pathways produce their effects at spinal level; 3) under what conditions these descending pathways are normally activated. The aim of this research proposal is to explore these issues by studying: 1) the spinal terminations of physiologically identified brain stem neurons at the light and electron microscopic (EM) levels; 2) the synaptic conductance changes evoked by focal brain stem stimulation in MZ and SG neurons; 3) the relationship of the descending axon terminals to the nerve endings of primary and second order neurons of known transmitter content and physiological activity; 4) the types of neurotransmitters released by brain stem neurons; 5) the activity of morphologically identified descending neurons in awake, behaving cats. Conventional single unit recordings, both extra- and intracellular, will be used to physiologically identify neurons. Iontophoresis of intracellular labels will be used to identify the recorded neurons for examination at light and EM levels. Finally, immunocytochemistry combined with anatomical tracers will be used to establish the relationship between descending connections and the various putative neurotransmitters found in the spinal SG. The results of these studies should lead to a basic understanding of the mechanisms whereby the CNS can modulate somatosensory information at the spinal level.